Bao Hanmei, Lv Feng, Liu Tianjun
Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomedical Materials, Tianjin 300192, China; Department of Clinical Pharmacology, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomedical Materials, Tianjin 300192, China.
Acta Biomater. 2017 Dec;64:279-289. doi: 10.1016/j.actbio.2017.09.033. Epub 2017 Sep 23.
Site-specific controlled release of exogenous angiogenic growth factors, such as recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. Here, we have developed an implant composed of spiral magnesium (Mg) and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The encapsulated protein could release continually for 4weeks with well preserved bioactivity. We compared the angiogenic effect produced by Mg-PLGA-rhbFGF with that of a PLGA implant loaded with rhbFGF (PLGA-rhbFGF). The incorporation of Mg in the implant raised the microclimate pH in the polymer, which preserved the stability of rhbFGF. Mg-PLGA-rhbFGF exhibited advantages over PLGA-rhbFGF implant in terms of a cytocompatibility evaluation. An in vivo angiogenesis test further confirmed the efficacy of released rhbFGF. HE, CD31 and α-SMA staining revealed that the controlled release of rhbFGF from the Mg-PLGA-rhbFGF implant was superior in promoting angiogenesis compared with that of the PLGA-rhbFGF implant. Four weeks post-implantation, the capillary density of the Mg-PLGA-rhbFGF group was significantly higher than that of the PLGA-rhbFGF, control and the normal group (p<0.05, p<0.01 and p<0.01, respectively). Furthermore, the limb blood perfusion ratios of the Mg-PLGA-rhbFGF and PLGA-rhbFGF groups were dramatically increased, at 99.1±2.9% and 80.7±3.2%, respectively, whereas the ischemic limb did not recover in the control group. The biocompatibility of the implants was also evaluated. In conclusion, Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery. The results suggest potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia.
Magnesium (Mg)-based implant has been already used in patients with critical limb ischemia. Site-specific controlled release of recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. We report here on a novel combination implant composed of spiral magnesium and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The preparation method does not involve any complex processes and results in a high encapsulation efficiency (approximately 100%). The degradation of metal Mg raise the microclimate pH in the PLGA polymer, which could well preserve the bioactivity of rhbFGF incorporated in the implant. Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery in rat limb ischemic model. This work marks the first report for controlled release of rhbFGF in combination with metal Mg, and suggests potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia.
外源性血管生成生长因子的位点特异性控释，如重组人碱性成纤维细胞生长因子（rhbFGF），已成为改善外周血管疾病的一种有前景的方法。在此，我们开发了一种由螺旋镁（Mg）和使用聚乳酸-乙醇酸共聚物（PLGA）制成的涂层组成的植入物，该涂层包裹有rhbFGF（Mg-PLGA-rhbFGF）。包裹的蛋白可以持续释放4周，且生物活性良好保存。我们比较了Mg-PLGA-rhbFGF与负载rhbFGF的PLGA植入物（PLGA-rhbFGF）产生的血管生成作用。植入物中镁的加入提高了聚合物中的微环境pH值，从而保持了rhbFGF的稳定性。在细胞相容性评估方面，Mg-PLGA-rhbFGF比PLGA-rhbFGF植入物具有优势。体内血管生成试验进一步证实了释放的rhbFGF的功效。苏木精-伊红（HE）、CD31和α-平滑肌肌动蛋白（α-SMA）染色显示，与PLGA-rhbFGF植入物相比，Mg-PLGA-rhbFGF植入物中rhbFGF的控释在促进血管生成方面更具优势。植入后4周，Mg-PLGA-rhbFGF组的毛细血管密度显著高于PLGA-rhbFGF组、对照组和正常组（分别为p<0.05、p<0.01和p<0.01）。此外，Mg-PLGA-rhbFGF组和PLGA-rhbFGF组的肢体血液灌注率显著增加，分别为99.1±2.9%和80.7±3.2%，而对照组的缺血肢体未恢复。还评估了植入物的生物相容性。总之，基于Mg-PLGA的rhbFGF持续局部递送可促进缺血后血管生成和血流恢复。结果表明Mg-PLGA-rhbFGF对组织缺血具有潜在的治疗作用。
镁（Mg）基植入物已用于严重肢体缺血患者。重组人碱性成纤维细胞生长因子（rhbFGF）的位点特异性控释已成为改善外周血管疾病的一种有前景的方法。我们在此报告一种新型组合植入物，它由螺旋镁和使用聚乳酸-乙醇酸共聚物（PLGA）制成的涂层组成，该涂层包裹有rhbFGF（Mg-PLGA-rhbFGF）。制备方法不涉及任何复杂过程，且封装效率高（约100%）。金属镁的降解提高了PLGA聚合物中的微环境pH值，这可以很好地保持植入物中rhbFGF的生物活性。基于Mg-PLGA的rhbFGF持续局部递送可促进大鼠肢体缺血模型中的缺血后血管生成和血流恢复。这项工作标志着首次报道rhbFGF与金属镁联合控释，并表明Mg-PLGA-rhbFGF对组织缺血具有潜在的治疗作用。
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